Clinical islet transplantation presents significant challenges and much research has been directed to improving its outcome. More than 500 patients with type 1 diabetes have received human islet transplantation worldwide and demonstrated improved quality-of-life afterwards. However, the wide application of human islet transplantation is still hindered by two major barriers, the limited supply of donor islets and inadequate means to prevent immune rejection of the transplanted cells. Immune rejection is a common cause of graft failure after islet transplantation. Although immunosuppressive drugs such as tacrolimus, sirolimus and mycophenolic acid (MPA) can prevent immune rejection in many cases, these drugs also impair insulin release from transplanted human islets and long-term injections of these drugs may cause loss-of-function in human islet cells, a status characterized as the primary non-function (PNF). Besides the immunosuppressive drugs, PNF can also be caused by inflammatory cytokines, the hypoxic environment and reactive oxygen species.
MPA is a commonly used immunosuppressive drug in human islet transplantation. MPA inhibits inosine 5′-monophosphate dehydrogenase (IMPDH), an essential enzyme mediating purine synthesis in T cells and B cells. MPA also induces down-regulation of anti-apoptotic factors such as B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra-large (Bcl-xL), and an accumulation of pro-apoptotic mediators such as caspase-3 and small mitochondria-derived activator of caspases (SMACs), suggesting that MPA may impair islet function through the activation of the apoptotic pathway in human islet cells.
It is desirable to develop a new immunosuppressive compound with less side effects and a therapy thereof for improving the outcome of cell and/or organ transplantation.